Project Summary This proposed 5-year study brings together Dr. Stokes? training in population health and research on tobacco use behaviors with additional training in tobacco regulatory science, cardiovascular (CV) epidemiology, advanced biostatistics, and applied data science. To this end, Dr. Stokes has assembled a multidisciplinary team of mentors and advisors to aid his training and studies. The K01 will support a complementary set of training activities, including formal coursework, participation in the Early Career Faculty Development Program, the NIH-funded Clinical and Translational Science Institute sponsored K-to-R PRIME program, and strong mentorship from experts in relevant fields, to help him in his professional development and transition to independence. Population-based evidence on the CV effects of e-cigarette use is sparse, and the particular components of e-cigarette aerosols that may be responsible for CV harm remain poorly elucidated. The proposed research will integrate state-of-the-art causal inference methods, mediation analyses, and unsupervised data clustering approaches with the study of CV effects of e-cigarette use. The applicant will 1) examine the association of e-cigarette use and product transitions with incident CV events; 2) estimate associations of e-cigarette use with risk factors and preclinical biomarkers of CV injury, and analyze biomarkers of exposure as potential mediators; and 3) identify unique biomarker signatures of e-cigarette exposure using a data-driven clustering approach, and associate clusters with preclinical biomarkers of CV injury. With high quality population data and novel statistical methods to optimally control for cigarette smoking and other tobacco product use, the results of this project will provide timely and rigorous evidence on the CV effects of e-cigarette use. Together with evaluating the mediating role of exposure biomarkers and clustered e- cigarette use behavior patterns, the results will inform Food and Drug Administration regulatory standards for product safety and guide primary and secondary public health interventions that aim to reduce tobacco-related CV harm. The methods and findings will also inform future studies focused on other non-cigarette tobacco products, such as little cigars, cigarillos, and smokeless tobacco products. The additional training and protected time afforded by the K01 will aid Dr. Stokes in making his transition to an independent investigator capable of securing R-series NIH funding.